The beta hemoglobinopathies do not become manifest until fetal globin (Hb F) is suppressed in infancy, and renewed production of fetal (5') globin decreases complications of these diseases. The need for additional therapeutics which stimulate high proportions of Hb F-containing red blood cells (F-cells) has been recently cited as an unmet priority. Short chain fatty acids (SCFAs) induce beta globin experimentally and in some patients. However, most SCFAs also inhibit erythroid cell growth, which limits the pool of cells in which fetal globin can be induced. Further, the need for IV infusions or large doses, due to rapid metabolism, has made the first SCFA therapies difficult for patient use. We have identified unusual SCFA derivatives, which induce fetal globin in transgenic mice and nonhuman primates, and also stimulate, rather than inhibit, hematopoietic cell proliferation. We hypothesize that mitogenic SCFAs which can be given more often, without dose limitations to prevent cell growth arrest, should induce higher levels of F-cells and beta globin than the growth-inhibitory SCFAs. Five SCFAD candidates with favorable oral PK profiles in baboons have been identified. The aims of this proposal are: 1) to determine which lead SCFA maximally induces F-cells and beta globin in nonhuman primates long-term, and whether there is additive activity between the novel SCFADs and hydroxyurea; 2) to identify additional T globin-inducing compounds using a computer-modeled pharmacophore, and to determine if any have greater potency, 3) to perform rational selection for preclinical development of candidates for the therapeutic induction of beta globin, and 4) to determine molecular mechanisms of cellular growth stimulation by the mitogenic SCFADs.